The present invention relates to novel therapeutic uses of a known compound, N-(2,6-disubstituted aromatic)-N'-pyridinyl ureas, its derivatives, and pharmaceutically acceptable salts. The present invention also relates to novel therapeutic uses of various other anticonvulsant drugs, their derivatives, and pharmaceutically acceptable salts. The present invention concerns a method for treating neurodegenerative diseases and disorders in a mammal in need of such treatment.
Such neurodegenerative diseases are, for example, Alzheimer's disease, Huntington's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis.
The present invention also covers treating neurodegenerative disorders termed acute brain injury. These include but are not limited to: stroke, head trauma, and asphyxia.
Stroke refers to a cerebral vascular disease and may also be referred to as a cerebral vascular incidence (CVA) and includes acute thromboembolic stroke. Stroke includes both focal and global ischemia. Also included are transient cerebral ischemic attacks and other cerebrovascular problems accompanied by cerebral ischemia. A patient undergoing carotid endarterectomy specifically or other cerebrovascular or vascular surgical procedures in general, or diagnostic vascular procedures including cerebral angiography and the like.
Other incidents are head trauma, spinal cord trauma, or injury from general anoxia, hypoxia, hypoglycemia, hypotension as well as similar injuries seen during procedures from embole, hyperfusion, and hypoxia.
The instant invention would be useful in a range of incidents, for example, during cardiac bypass surgery, in incidents of intracranial hemorrhage, in perinatal asphyxia, in cardiac arrest, and status epilepticus.
A skilled physician will be able to determine the appropriate situation in which subjects are susceptible to or at risk of, for example, stroke as well as those suffering from stroke for administration by methods of the present invention.
After ischemia of the brain in vivo many changes take place. There is a rapid loss of synaptic activity, a large shift in extracellular voltage, a release of the neurotransmitter glutamate, and a loss of ion homeostasis. The excess release of glutamate may be especially important in ischemic injury. Glutamate is an excitotoxin, meaning that overstimulation of glutamate receptor-linked channels allows excess calcium and sodium influx into neurons leading to neuronal death.
The overstimulation of receptors is thought to be involved in the etiology of several neurological disorders, i.e., epilepsy and cerebral ischemia. Evidence is also accumulating that the brain damage associated with anoxia, stroke, hypoglycemia, epilepsy, and perhaps neurodegenerative illnesses such as Alzheimer's or Huntington's diseases may be at least partially produced by excessive activation of N-methyl-D-aspartic acid (NMDA) receptors (Kemp J A, Foster A C, Wong E H F, Trends in Neurosciences 1987;10(7):294-8).
The present invention employs the use of anticonvulsant compounds, such as the compounds of Formula I which are phenyl pyridinyl ureas as a method of blocking or delaying damage to neurons from conditions similar to ischemia. It is believed that by preventing neuronal damage, the compounds of Formula I, alone or together with a pharmaceutically acceptable carrier, can be used to treat neurological diseases such as Alzheimer's disease, Huntington's disease, Parkinson's disease, myotropic lateral sclerosis, and disorders such as stroke, head trauma, and asphyxia. The present invention is also directed to similar uses and methods of treatment employing other anticonvulsant compounds disclosed herein.
Various substituted phenyl pyridinyl ureas have been described but none having neuroprotective activity. For example, Bruce M I, Zwar J A, Proc Roy Soc (London), Sec. B. 165 (999), 1966;245-65 disclose many N-mono- and N,N'-disubstituted ureas having cytokinin activity. N-(3,4-dichlorophenyl)-N'-3- and 4-pyridinyl ureas show such activity whereas the corresponding 2,5-dichloro compounds were inactive. In general, the authors concluded that phenyl ring substitution enhanced activity with meta substituents providing highest activity and ortho substituents lowest activity.
German Patent Publication 2,928,485 also describes various ureas including N-(3-chloro-4-trifluoromethyl-phenyl)-N'-3- and 4-pyridinyl ureas as being useful for inhibiting lipid absorption.
French Patent Publication 2,155,856 teaches various 2-pyridinyl ureas including N-(3,4-dichlorophenyl)-N'-2-pyridinyl urea as having antiinflammatory and analgesic activity.
U.S. Pat. No. 4,629,731 covers the phenyl pyridinyl urea compounds of the instant invention, methods for preparing them, and their use as an anticonvulsant. The term convulsions is intended to mean the characteristic body movements which are associated with the group of chronic central nervous system disorders termed epilepsies. The patent is hereby incorporated by reference.
There is no disclosure in the above references to suggest the present invention's novel uses of compounds of U.S. Pat. No. 4,629,731 to treat neurodegenerative diseases and disorders in a mammal in need of such treatment.